Autoimmune diseases result from the inappropriate recognition of self antigens by T cells. While recent treatment strategies have focused on modulating signals through the antigen specific T cell receptor (TCR), the complex nature of the TCR has impeded the development of such approaches. A better understanding of the TCR components and the development of animal models in which the TCR components can be qualitatively and quantitatively manipulated will aid in the development and testing of new treatments for autoimmune disease. The TCR is composed of at least 6 different chains involved in antigen recognition or signal transduction. The zeta chain of the TCR is a particularly potent signaling molecule due to the 3 repeated activation motifs (ITAMS) in its intracytoplasmic tail. To study the role of zeta-chain in T cell responses, we have created mice in which the gene encoding zeta-chain has been inactivated by homologous recombination (zeta-/-). We have also generated mice expressing transgenes encoding normal or truncated forms of zeta (missing all three or particular ITAMs). Alternatively, we have generated transgenic mice expressing the gamma chain of the FcR, that is homologous to zeta and which has been found associated with the TCR in certain T cell populations. The ability to breed these zeta related transgenes into the zeta-/- background makes it possible to specifically examine the role of zeta in T cell response in vivo. Moreover, since zeta controls the amount of TCR complexes on the cell surface, this system also allows us to address the relation between TCR levels (extent of signalling) and specific T cell responses. Using a combination of approaches we are examining the role of zeta-chain and zeta-related molecules in T cell tolerance, activation and development. Future experiments will involve breeding these zeta-related molecules into mice bearing transgenes encoding TCRs with autoreactive specificities. Such studies should result in a better understanding of T cell tolerance and provide important animal models for testing new TCR-directed therapies for autoimmune disease. 1. Shores, E.W. and P.E. Love. 1995. Int. Rev. Immunol.(in press). 2. Love, P.E., E.W. Shores, et. al 1994. J. Exp. Med 179:1485. 3. Shores, E.W., et. al 1994. Science 266:1047.